Interview #1: 'What Animals Can Teach'

Jaylan Turkkan, PhD, an experimental psychologist, conducted research with baboons and other animals at The Johns Hopkins University School of Medicine before becoming chief of the Behavioral Services Research Branch of the National Institute of Drug Abuse (NIDA) in 1994.(15)

Q. Why use animals to study human health?

A. There are studies that can contribute enormous benefits that you could never do with people under the right kinds of controls to answer the questions being posed.

Q. What kinds of studies?

A. For example, if you wanted to find out whether raising children in an impoverished environment causes them to have a lower IQ later, you would never subject children to situations where they have nothing to do for long stretches of time to see how it affects their later intelligence.

The long-term consequences of using methamphetamines, for another example. You can’t give methamphetamines to kids to see what it does to their learning, but with animals, you can study them over the entire course of their much shorter life spans. This affords an unusual opportunity to simulate human situations where people are exposed to things repeatedly for long periods of time that you just can’t study in people.

Q. What kinds of animal-based drug abuse studies is NIDA sponsoring?

A. We want to know whether drugs are enticing, apart from the social pressure to use them. Monkeys and rats have no social pressures to use drugs, so you can eliminate those social factors and ask the "does it feel good" question without getting into peer pressure and I-want-to-diss-my-parents and all that. But even animals do have social factors that can tell us about ourselves – for example, whether they use more or less drugs according to whether they are the leaders of the pack or not. You can manipulate animals’ social conditions in very ordered and careful ways.

Q. Are there other situations where animals are better subjects than people?

A. There are also studies in which people are unwilling to hold still or show up for weeks at a time. You might need to subject animals to very painstaking situations in which they respond to colors and lights for two or three hours in experimental chambers to see how the effects develop over the life of the animal. You could never do that with children. You could hardly do it with people of any age. You’d never get that kind of attention. Just getting people to show up more than once can be a major challenge.

Q. Where does genetic research with animals come in?

A. The variability of people’s genetic endowment is hard to eliminate, but you can often eliminate it when you use animals. You can control for genetics very carefully in animal studies by having animals from the same litter or through the use of transgenic animals. Scientists have been doing litter-mate studies for decades.

But you can’t just control the genetic makeup and then imagine that stress and handling won’t have some kind of important interaction with the genetics. In a recent issue of Science, John Crabbe, PhD, director of the Portland Alcohol Research Center, demonstrated that, even with genetically identical litter-mates, when different people handled these identical animals in different laboratories, the animals performed differently on behavioral tests.(4) That’s probably because handling is a huge factor in how animals settle into a laboratory and how well they do in experiments.

The point is that behavioral outcomes can be very sensitive to interaction with the environment, that we aren’t simply the result of genetic codes hard-wired into us. It’s a good reminder to us that there is so much that we still don’t understand about the interaction between behavior and the environment.

Interview #2: 'Monkeys on Cheeseburgers'

Jay Kaplan, PhD, professor of Pathology and Anthropology at Wake Forest University, has used monkeys for about 20 years to investigate how behaviors influence susceptibility to disease. Much of his work is in collaboration with Stephen Manuck, PhD, of the University of Pittsburgh. (9,10)

Q. Tell us about your research.

A. We use monkeys as surrogates for humans to investigate behavioral influences on susceptibility to atherosclerosis. This is an inflammatory process that involves the development of fibrous and fatty plaques in the inner lining of arteries. When it affects the heart, atherosclerosis leads to coronary heart disease, the single largest killer of men and women of middle age and older. Our research shows that, within the same environment and on the same "cheeseburger diet," some monkeys develop larger lesions than others. The pattern we see is related to individual differences in the animals’ social status, which is based on their aggressive and submissive behaviors.

Q. Why not do the research with people?

A. Atherosclerosis doesn’t develop in people in just a few years, as it does in monkeys. It progresses over decades. There’s no way it could be studied over that period of time. A second issue is that working with animals allows you to use diagnostic techniques that you couldn’t use on people who have not yet shown clinical symptoms of disease. A third issue is experimental control. With animals, there are things you can do in assigning them to experimental groups, diets, and environments that you can’t do with humans.

Q. Why monkeys?

A. Monkeys are similar to people in social behavior and physiology, and both are important for our research. In terms of social behavior, they resemble people across the broad dimensions of social status and affiliation. In monkeys, the expression of behavior along these dimensions nearly matches the complexity seen in humans. And, it happens that epidemiologic studies often identify these two dimensions in conjunction with coronary heart disease risk in people.

Q. What do you do to the monkeys?

In addition to feeding them a diet that resembles our own, we house them in same-sex groups of five or six, where they form status hierarchies by competitive interaction. They compete over anything, sometimes over nothing. Most of their hostile behavior is manifested in ritualized threat gestures, and the animals being threatened might respond by cowering and showing a fear grimace. Some animals are reliably and predictably winners and others are reliably and predictably losers in these confrontations.

In sum, it all shakes down into a pecking order. As part of our experimental manipulation, we sometimes also rotate the monkeys into new groups on a monthly basis, forcing them to re-compete for status and re-establish their networks of social support.

It turns out that high or low status in the dominance hierarchy predicts the extent of the monkeys’ atherosclerotic lesions. So, the salient factor is social status. We usually do separate experiments with males and females, as the effects of status on atherosclerosis are different in the two sexes. Our work is directed toward identifying the factors that lead to susceptibility and resistance in each sex.

Q. Are all the similarities behavioral? Do monkeys also resemble humans in the way they respond to fatty diets?

A. Yes, and they also resemble humans in the development of atherosclerosis. Lesions develop first in the peripheral arteries, then in the arteries of the heart and brain. When atherosclerosis becomes severe, monkeys – like people – have heart attacks and, occasionally, strokes.

Another element, and one that is important in thinking about women’s health, is that female monkeys have a 30-day menstrual cycle with a hormonal profile similar to that observed in women.

Of course, anyone who has been to a zoo knows that monkeys are also similar to us in the way their facial expressions, postures, and vocalizations reflect their internal emotions. It becomes fairly easy for an investigator to determine the mood of these animals because their social expressions and emotions are so much like our own.

Q. What have the monkeys taught you so far?

A. In male monkeys, we’ve found that environments that provoke competitive interactions place the more dominant individuals at increased risk for atherosclerosis. In men, this points to certain groups: aggressive, competitive, successful males who are exposed to stressful situations that challenge their status are the ones that are at high risk. This risk is caused by excessive activation of the sympathetic nervous system, as the effect in male monkeys can be eliminated by drugs that block stimulation of the sympathetic nervous system.

Among females it is the subordinate animals that are at the highest risk. This outcome is probably related to the high incidence of abnormal menstrual cycles and resulting estrogen deficiency in such monkeys, because the atherosclerosis effects can be prevented if the animals are treated with estrogen. We believe that our studies using monkeys have unmasked a potential risk factor for atherosclerosis in premenopausal women that would not otherwise be recognized: ovarian impairment and relative estrogen deficiency.

In the monkeys, this state is associated with the stress of social subordination, as subordinate females have enlarged adrenal glands and produce large amounts of the stress hormone cortisol. Based on our findings, we speculate that psychosocial stress may similarly lead to subclinical ovarian impairment in some young women, which in turn may predispose them to develop atherosclerosis at an accelerated rate.

Supporting our speculation are recent studies showing that up to 25 percent of young women experience periods of subclinical ovarian function, the most common cause of which is probably stress. Furthermore, it is now known that, contrary to common belief, substantial atherosclerosis develops in young women. By age 35, one-third of all women have significant coronary artery atherosclerosis. Our studies lead us to think that this "premature" development of atherosclerosis reflects, in part, behavioral factors and that the affected women are vulnerable to subsequent clinical events.

Rats and People from Infancy to Old Age:

Events that predict degeneration of the brain and loss of capacity in rats appear to do so in humans as well, research findings suggest.

Michael Meaney, PhD, associate director of research at McGill University’s Douglas Hospital Research Center in Montreal, says his research team is able to predict from the level of corticosterone, a cortisol-like stress hormone, in middle-aged rats (before they are two years old) which ones will become diabetic or have hypertension, and in which ones the memory center of the brain, the hippocampus, will degenerate and result in learning and memory problems. (1,6,15,16)

"It all works," Meaney says. "You find that the basic predictors, or biomarkers, of degenerative disorders are very much the same in rats as they are in humans. The higher your level of cortisol the smaller your hippocampus and the more impaired are certain forms of memory."

Douglas Hospital researchers study rats across the entire life span. "What we’ve also shown," Meaney says, "is that you get exactly the predicted relationship: the animals that were licked more in early life don’t release as much corticosterone, and because of this their hippocampi are more likely to survive in their later years. So now we are trying to use antidepressant drugs with aging rats to see if ultimately we may be able to spare the hippocampi of older people who may be in a similar dangerous state."

It is Meaney’s work that showed the beneficial health effects of maternal licking in rat pups (see Facts of Life, Vol. 4, No. 4, May 1999) and that rats reared in an emotionally-impoverished environment react to stress much more radically throughout their lives. But the process is largely reversible, he says. "If we put these offspring in an enriched environment, it almost completely reverses these characteristics. It’s truly impressive the degree to which you can reverse the harm from lack of adequate nurturing during early life."

He also says his research demonstrates that we should stop blaming our genes for as much as we do. Many believe that if it’s genetic, it’s immutable, he says. "Of course, that’s completely untrue. Instead, we should think of genes as being like any other molecule that can be more or less active. You can inherit it, but that’s only part of the story. What are going to determine its activity in many ways are the behaviors.

"Within the brain there are a number of genes that are active, and they influence the way you respond to stress. But the mother’s behavior toward her offspring in early life determines the activity of those particular genes. One of the things we know from the rats is that from a lot of licking, rats’ brains grow more synaptic connections. If there is environmental enrichment in adolescence, it increases the number of connections in the hippocampus."

Diet + Exercise + Stress = Infertility

Reducing food intake decreases sex hormone levels. So does extreme exercising and everyday social stress. The worst is a combination of all three, even at mild levels. We know because monkeys told us.

The combination of these stresses suppressed the reproductive function of 90 percent of the female monkeys in studies at the Oregon Regional Primate Research Center in Portland. "The female monkeys lost their menstrual cycles for various periods of time," says Judy Cameron, PhD, principal investigator in studies yet to be published. Male monkeys also showed significant decreases in testicular hormone levels.(2)

"There’s a significant take-home message for us human beings that comes straight out of monkey work," says Cameron. "Here in the United States, many of us diet a little bit, exercise a little bit, and have everyday kinds of stress. The message from the monkeys is that a combination of those three is actually a powerful inhibitor of reproduction."

The results are replicated in people. In fact…

"What makes it good to start with monkeys is that you can reduce their calorie intake or make them do exercises and know they will stick to it," says Cameron. "Another problem with people is that if you do get an effect from dieting, you don’t know whether it is the diet or because they had some major psychological stress at the time."

Cameron on her major findings thus far:

Nutrition: "To keep reproductive hormone levels high you need to take in a good amount of calories – it doesn’t really matter whether it’s carbohydrates, proteins, or fat – and eat frequently rather than waiting long between eating. Over-eating appears to have no negative consequences (on reproduction), from the small amount of work we’ve done on that so far."

Exercise: "We’ve trained monkeys to run on treadmills and they love it. What the experiments show is that you can suppress reproduction with extreme amounts of running, the equivalent of what an Olympic marathon runner would do in practice. But the running most people do when they’re just trying to stay in shape has no negative impact on reproductive function. It’s safe to do."

Stress: "We move the monkeys to a new room where they don’t know any of the 40 or 50 other monkeys. About 20 percent of them experience psychosocial stress that suppresses their reproductive functions, probably similar to what people feel when they move to a new school or new workplace."

"For years we’ve known that the reproductive system closes down if you are undernourished or very stressed or you exercise a lot," says Cameron, "but that was believed to be only under extreme conditions. Our more recent work shows, with monkeys at first and then in humans, that the reproductive axis is very sensitive. Even mild forms of stress can have an impact on the reproductive function."

Much of her research now focuses on how quickly fertility is influenced by diet, exercise, and stress, and whether women who are trying to become pregnant or having in vitro fertilization could improve their chances by changing these aspects of their lifestyle. Says Cameron: "Based on the findings from monkeys, we’re trying to develop therapy to restore fertility by slightly increasing calorie intake and slightly decreasing social stress levels, instead of putting women on drugs."

Nicotine-Addicted Rats

"Adolescents and adults may smoke cigarettes for different reasons. It’s important to know what those reasons are if we want to get young people to stop smoking or – better yet – never start.

"We’ve all heard about peer pressures and other social and psychological pressures, but that’s probably not the whole story. In our lab we’ve launched a research project that should give us a better understanding of how much the differences between adolescents and adults stem from biological bases and behavioral responses to nicotine, as opposed to peer and social pressures.

"We inject adolescent rats with the drug to see what effects it has on them and their behaviors. That’s the only way to tease apart the basic biological and behavioral responses to nicotine without the social pressures. Human research unavoidably includes those social pressures."

Interview with Neil Grunberg, PhD, professor of medical psychology, clinical psychology, and neuroscience at the Uniformed Services University of the Health Sciences, August 1999. (4)

The Research:

1. Caldji C, Meaney MJ, et al. (April 28, 1998). "Maternal Care during Infancy Regulates the Development of Neural Systems Mediating the Expression of Fearfulness in the Rat." Proceedings of the National Academy of Sciences USA, 95 (9): 5335-5340.
2. Cameron JL. (February 1997). "Stress and Behaviorally Induced Reproductive Dysfunction in Primates." Seminars in Reproductive Endocrinology, 15(1): 37-45.
3. Corrigall WA, et al. (1992). "The Mesolimbic Dopaminergic System Is Implicated in the Reinforcing Effects of Nicotine." Psychopharmacology, 107: 285-289.
4. Crabbe JC, et al. (June 4, 1999). "Genetics of Mouse Behavior: Interactions with Laboratory Environment." Science, 284: 1670-1672.
5. Faraday MM and Grunberg NE. (February 1999). "The Role of Biobehavioral Animal Models: A Mainstay in Nicotine, Tobacco Research." Society for Research on Nicotine & Tobacco Newsletter, 310.
6. Francis DD and Meaney MJ. (February 1999). "Maternal Care and the Development of Stress Responses." Current Opinion in Neurobiology, 9(1): 128-134.
7. Gallagher M and Nicolle MM. (November 30, 1993). "Animal Models of Normal Aging: Relationship between Cognitive Decline and Markers of Hippocampal Circuitry." Behavioral Brain Research, 57(2): 155-162.
8. Gallagher M and Rapp PR. (1997). "Use of Animal Models To Study the Effects of Aging on Cognition." Annual Review of Psychology, 48: 339-370.
9. Kaplan JR and Manuck SB. (1998). "Monkeys, Aggression, and the Pathobiology of Atherosclerosis." Aggressive Behavior, 24: 323-334.
10. Kaplan JR, et al. (1996). "Psychosocial Factors, Sex Differences, and Atherosclerosis: Lessons from Animal Models." Psychosomatic Medicine, 58: 598-611.
11. Matthews DB, et al. (August 1996). "Ethanol Impairs Spatial Cognitive Processing: New Behavioral and Electrophysiological Findings." Current Directions in Psychological Science, 5(4): 111-115.
12. Rose JE and Corrigall WA. (1997). "Nicotine Self-Administration in Animals and Humans: Similarities and Differences." Psychopharmacology, 130: 28-40.
13. Rowe W, Meaney MJ, et al. (September 1997). "Antidepresssants Restore Hypothalamic-Pituitary-Adrenal Feedback Function in Aged, Cognitively-Impaired Rats." Neurobiological Aging, 18(5): 527-33.
14. Tannenbaum BM, Meaney MJ, et al. (December 1997). "High-fat Feeding Alters Both Basal and Stress-Induced Hypothalamic-Pituitary-Adrenal Activity in the Rat." American Journal of Physiology, 273: E1168-1177.
15. Turkkan J. (1990). "Paradoxical Experimental Outcomes and Animal Suffering." Behavioral and Brain Sciences, 13: 42-43.

Academy of Behavioral Medicine Research
Academy of Psychosomatic Medicine
American College of Neuropsychopharmacology
American Psychiatric Association
American Psychological Association
American Psychological Association-Division 38
American Psychosomatic Society
American Society of Psychiatric Oncology
College on Problems of Drug Dependence
International Psycho-Oncology Society
International Society for Traumatic Stress Studies
Society of Behavioral Medicine
Society for Developmental and Behavioral Pediatrics
Society for Public Health Education
Society for Research on Nicotine and Tobacco

The Center for the Advancement of Health, , a nonprofit institute, promotes the science that explores health as a complex and dynamic system of relationships among biology, behavior, psychology, and social context and works to integrate this knowledge into public awareness, health care policy, and health care practice. The Center was founded by the John D. and Catherine T. MacArthur Foundation and the Nathan Cummings Foundation, which continue to provide core funding.

For more information contact:
Petrina Chong Director of Communications
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